Citations

Abstract The presence of regulatory T cells (Treg) in solid tumors is known to play a role in patient survival in ovarian cancer and other malignancies. We assessed inherited genetic variations via 749 tag single-nucleotide polymorphisms (SNP) in 25 Treg-associated genes (CD28, CTLA4, FOXP3, IDO1, IL10, IL10RA, IL15, 1L17RA, IL23A, IL23R, IL2RA, IL6, IL6R, IL8, LGALS1, LGALS9, MAP3K8, STAT5A, STAT5B, TGFB1, TGFB2, TGFB3, TGFBR1, TGRBR2, and TGFBR3) in relation to ovarian cancer survival. We analyzed genotype and overall survival in 10,084 women with invasive epithelial ovarian cancer, including 5,248 high-grade serous, 1,452 endometrioid, 795 clear cell, and 661 mucinous carcinoma cases of European descent across 28 studies from the Ovarian Cancer Association Consortium (OCAC). The strongest associations were found for endometrioid carcinoma and IL2RA SNPs rs11256497 [HR, 1.42; 95% confidence interval (CI), 1.22–1.64; P = 5.7 × 10−6], rs791587 (HR, 1.36; 95% CI, 1.17–1.57; P = 6.2 × 10−5), rs2476491 (HR, = 1.40; 95% CI, 1.19–1.64; P = 5.6 × 10−5), and rs10795763 (HR, 1.35; 95% CI, 1.17–1.57; P = 7.9 × 10−5), and for clear cell carcinoma and CTLA4 SNP rs231775 (HR, 0.67; 95% CI, 0.54–0.82; P = 9.3 × 10−5) after adjustment for age, study site, population stratification, stage, grade, and oral contraceptive use. The rs231775 allele associated with improved survival in our study also results in an amino acid change in CTLA4 and previously has been reported to be associated with autoimmune conditions. Thus, we found evidence that SNPs in genes related to Tregs seem to play a role in ovarian cancer survival, particularly in patients with clear cell and endometrioid epithelial ovarian cancer. Cancer Immunol Res; 2(4); 332–40. ©2014 AACR.

BackgroundHenoch‐Schönlein purpura (HSP) is a vasculitis that can affect the skin and kidneys. It is characterized by immunoglobulin (Ig) A‐predominant deposition in small blood vessels. To our knowledge, there has been no comparison of direct immunofluorescence (DIF) findings in skin and kidney biopsy specimens.MethodsWe retrospectively studied 21 adults with HSP who had IgA deposition in the skin and kidneys. The skin and kidney DIF findings were compared and tested for an association with the progression of renal disease.ResultsMean age of the patients was 51.4 years. Follow‐up data were available for 19 patients, of whom 5 had progression to chronic kidney disease or renal failure. Concordance between DIF findings on skin and renal biopsies was 100% for IgA, 80% for C3, 80% for IgG, 71% for IgM and 53% for fibrinogen. A worse renal outcome was associated with renal IgG deposition (p = 0.04). A trend for worse renal outcome was found with renal fibrinogen and skin IgM deposition (p = 0.10 and 0.14, respectively).ConclusionsIn this retrospective study of adult HSP, the concordance between DIF findings in skin and kidney specimens was low‐moderate. Further study is required to elucidate the mechanisms responsible for these differences in Ig deposition.

AbstractPurposeThe goals of part 2 of the study presented here were 1) to assess whether there is a difference in failure mode of different thicknesses (2.0, 1.5, 1.0, and 0.5 mm) of anatomically standardized full contour monolithic lithium disilicate restorations for posterior teeth, and 2) to assess if there is a difference among various crown thicknesses when these restorations are subjected to dynamic load forces common for posterior teeth.Materials and MethodsFour groups (n = 10), each with a different thickness of anatomically appropriate all‐ceramic crowns, were to be tested as established from the statistical analysis of the preliminary phase. Group 1: 2.0 mm; group 2: 1.5 mm; group 3: 1.0 mm; group 4: 0.5 mm. The specimens were adhesively luted to the corresponding die, and underwent dynamic cyclic loading (380 to 390 N) completely submerged in an aqueous environment until a failure was noted by graphic recording and continuous monitoring.ResultsThere was a statistically significant difference of the fatigue cycles to failure among four groups (p < 0.001; Kruskal‐Wallis test). The mean number of cycles to fail for 2.0 mm specimens was 17 times more than the mean number of cycles to fail for 1.0 mm specimens and 1.5 times more than the mean number of cycles to fail for 1.5 mm specimens. The 0.5 mm specimens failed with one cycle of loading. A qualitative characteristic noted among the 2.0 mm specimens was wear of the area of indenter contact followed by shearing of the material and/or crack propagation.ConclusionBased on the findings of this study, it may be reasonable to consider a crown thickness of 1.5 mm or greater for clinical applications of milled monolithic lithium disilicate crowns for posterior single teeth.

Key Points Pomalidomide plus low-dose dexamethasone significantly improved PFS vs pomalidomide alone in relapsed and refractory multiple myeloma. Pomalidomide plus low-dose dexamethasone is an important new treatment option for RRMM patients who have received multiple prior therapies.

AbstractBackgroundMortality rates in patients with bullous pemphigoid (BP) are higher than those in age‐matched counterparts. However, the specific causes of death in BP subjects have not been evaluated systematically.ObjectivesWe sought to characterize the causes of death in patients with BP as recorded by death certificate and to compare these with death data for age‐ and location‐matched control subjects.MethodsThis was a retrospective cohort analysis conducted in a large tertiary referral center. Twenty‐seven participants who had a confirmed antemortem diagnosis of BP, were residents of Olmsted County, Minnesota, and had died between January 1, 1999, and January 1, 2009, were included in the study. Underlying cause of death and multiple causes of death data for the study population were compared with data sourced from the Centers for Disease Control and Prevention (CDC) for a control group matched by age and geographic location of origin by International Classification of Diseases, 10th Revision (ICD‐10) block, and specific ICD‐10 codes.ResultsComparisons of specific ICD‐10 codes revealed increased rates of sepsis (P = 0.031), dementia (P = 0.049), and major depressive disorder (P = 0.005) in the study group. The collective incidence of ICD‐10 codes for infections indicated that infections were more frequent contributors to death in the study group (P = 0.035).ConclusionsClinicians should be mindful of contributors to death in patients with BP and might consider screening for mental health issues, educating patients on the early symptoms of sepsis, and minimizing risk factors for infection.

SummaryAutologous stem‐cell transplant has been widely used to treat patients with AL amyloidosis. However, transplant‐related mortality rates are high, and a recent randomized trial suggested that non‐transplant regimens produced comparable results with less toxicity. In order to define the role of patient selection in stem cell transplantation, we evaluated 78 consecutive AL amyloidosis patients transplanted at our centre. Transplant‐related mortality occurred in 11·5%. Complete haematological response and organ response were achieved in 56% and 60%. Median overall survival was significantly lower for patients with brain‐type natriuretic peptide (BNP) >300 pg/ml (17·5 months vs. not‐reached) (P = 0·0004), troponin‐I >0·07 ng/ml (13·5 months vs. not‐reached) (P = 0·00001) and those not achieving a complete haematological response (88 months vs. not‐reached) (P = 0·0345); high BNP and troponin‐I were the most important predictive factors in a multivariate analysis. Based on this study, patients with BNP <300 pg/ml and/or normal levels of troponin‐I should be considered transplant candidates.

Abstract A missense single-nucleotide polymorphism (SNP) in the immune modulatory gene IL1A has been associated with ovarian cancer risk (rs17561). Although the exact mechanism through which this SNP alters risk of ovarian cancer is not clearly understood, rs17561 has also been associated with risk of endometriosis, an epidemiologic risk factor for ovarian cancer. Interleukin-1α (IL1A) is both regulated by and able to activate NF-κB, a transcription factor family that induces transcription of many proinflammatory genes and may be an important mediator in carcinogenesis. We therefore tagged SNPs in more than 200 genes in the NF-κB pathway for a total of 2,282 SNPs (including rs17561) for genotype analysis of 15,604 cases of ovarian cancer in patients of European descent, including 6,179 of high-grade serous (HGS), 2,100 endometrioid, 1,591 mucinous, 1,034 clear cell, and 1,016 low-grade serous, including 23,235 control cases spanning 40 studies in the Ovarian Cancer Association Consortium. In this large population, we confirmed the association between rs17561 and clear cell ovarian cancer [OR, 0.84; 95% confidence interval (CI), 0.76–0.93; P = 0.00075], which remained intact even after excluding participants in the prior study (OR, 0.85; 95% CI, 0.75–0.95; P = 0.006). Considering a multiple-testing–corrected significance threshold of P &lt; 2.5 × 10−5, only one other variant, the TNFSF10 SNP rs6785617, was associated significantly with a risk of ovarian cancer (low malignant potential tumors OR, 0.85; 95% CI, 0.79–0.91; P = 0.00002). Our results extend the evidence that borderline tumors may have a distinct genetic etiology. Further investigation of how these SNPs might modify ovarian cancer associations with other inflammation-related risk factors is warranted. Cancer Res; 74(3); 852–61. ©2013 AACR.

Objective To evaluate the association of perioperative blood transfusion ( PBT ) with survival after nephrectomy. Patients and Methods We identified 2318 patients who underwent partial or radical nephrectomy at M ayo C linic between 1990 and 2006. PBT was defined as transfusion of allogenic red blood cells during surgery or postoperative hospitalisation. Survival was estimated using the K aplan– M eier method and compared with the log‐rank test. Cox proportional hazards regression models were used to evaluate the association of PBT with outcome. Results In all, 498 patients (21%) received a PBT . The median (interquartile range) number of units transfused was 3 (2, 5). Patients receiving a PBT were significantly older at surgery ( P < 0.001), more likely to be female ( P < 0.001), with more frequent symptomatic presentation ( P < 0.001), worse E astern C ooperative O ncology G roup performance status ( P < 0.001), and more frequent adverse pathological features, such as high nuclear grade ( P < 0.001), locally‐advanced tumour stage ( P < 0.001) and lymph node invasion ( P < 0.001). The median follow‐up was 9.1 years. Receipt of a PBT was associated with adverse 5‐year cancer‐specific (68% vs 92%; P < 0.001) and overall (56% vs 82%; P < 0.001) survival. On multivariate analyses, PBT remained associated with higher risk of death from any cause (hazard ratio [ HR ] 1.23; P = 0.02). Among patients who received a PBT , an increasing number of units transfused was independently associated with increased all‐cause mortality ( HR 1.08; P = 0.001). Conclusion PBT is associated with a significantly increased risk of mortality after nephrectomy. While external validation is needed, continued efforts to minimise the use of blood products in these patients are warranted.